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Analysis helps quantify HU use in SCA
Photo by Zak Hubbard
Results of a retrospective study reinforce the idea that hydroxyurea (HU) is underused in US patients with sickle cell anemia (SCA).
Researchers analyzed data from an insurance claims database and identified 570 patients with probable SCA who were available for follow-up and likely would have benefitted from receiving HU.
Less than a quarter of those patients actually received the drug within a year of their third visit to a hospital seeking treatment for pain crises.
The researchers noted that these data may not be representative of the US population because the analysis does not include uninsured patients or publicly insured patients.
Nicolas Stettler, MD, of the Lewin Group in Falls Church, Virginia, and his colleagues conducted this research and reported the results in a letter to JAMA.
The researchers noted that the 2014 National Heart, Lung, and Blood Institute guidelines recommend using HU to treat all adults with SCA who experience 3 or more moderate-to-severe pain crises within a year. This is a “strong” recommendation based on high-quality evidence reviewed in 2008.
Despite this recommendation, it is thought that HU is underused, although the extent of its use has been unclear.
With that in mind, Dr Stettler and his colleagues examined the use of HU when indicated for SCA in the Optum Normative Health Informatics database. This database is a nationwide sample of commercial health and pharmacy claims from more than 36 million residents in all 50 states and Washington, DC.
The researchers identified adults ages 18 and older with 1 or more inpatient or outpatient claims for SCA between January 2009 and June 2013.
The team selected patients when they had 3 or more hospitalizations, emergency department visits, or both within 12 months that included 1 of the 5 most frequent diagnosis codes used for patients with SCA and pain crises.
Treatment was defined as filling 1 or more HU prescriptions during the 3, 6, or 12 months of continued enrollment following the third episode.
Of the enrolled population (n=26,631,901), the researchers identified 2086 adults with probable SCA. Of these patients, 677 had at least 3 pain-related hospitalizations or emergency department visits within 12 months, and 570 had at least 3 months of coverage after the third episode.
Among those 570 patients, 86 (15%) were treated with HU within 3 months of their third encounter. The percentage of treated patients increased slightly to 18% at 6 months and to 23% at 12 months.
The researchers noted that there are several barriers to HU treatment, including fear of adverse events, lack of clinician training, and failure to engage in shared decision-making.
The team also pointed out that their data do not include the uninsured or publicly insured population, which may have more limited access to healthcare or awareness of treatment options than the patients studied. So these findings may not be representative of the entire US population with SCA and may be a conservative estimate of the HU treatment gap.
To address this gap, it may be necessary to enhance patient outreach and clinician training and develop healthcare quality measures aimed at increasing the use of HU for all patients who would benefit, the researchers said. 
Photo by Zak Hubbard
Results of a retrospective study reinforce the idea that hydroxyurea (HU) is underused in US patients with sickle cell anemia (SCA).
Researchers analyzed data from an insurance claims database and identified 570 patients with probable SCA who were available for follow-up and likely would have benefitted from receiving HU.
Less than a quarter of those patients actually received the drug within a year of their third visit to a hospital seeking treatment for pain crises.
The researchers noted that these data may not be representative of the US population because the analysis does not include uninsured patients or publicly insured patients.
Nicolas Stettler, MD, of the Lewin Group in Falls Church, Virginia, and his colleagues conducted this research and reported the results in a letter to JAMA.
The researchers noted that the 2014 National Heart, Lung, and Blood Institute guidelines recommend using HU to treat all adults with SCA who experience 3 or more moderate-to-severe pain crises within a year. This is a “strong” recommendation based on high-quality evidence reviewed in 2008.
Despite this recommendation, it is thought that HU is underused, although the extent of its use has been unclear.
With that in mind, Dr Stettler and his colleagues examined the use of HU when indicated for SCA in the Optum Normative Health Informatics database. This database is a nationwide sample of commercial health and pharmacy claims from more than 36 million residents in all 50 states and Washington, DC.
The researchers identified adults ages 18 and older with 1 or more inpatient or outpatient claims for SCA between January 2009 and June 2013.
The team selected patients when they had 3 or more hospitalizations, emergency department visits, or both within 12 months that included 1 of the 5 most frequent diagnosis codes used for patients with SCA and pain crises.
Treatment was defined as filling 1 or more HU prescriptions during the 3, 6, or 12 months of continued enrollment following the third episode.
Of the enrolled population (n=26,631,901), the researchers identified 2086 adults with probable SCA. Of these patients, 677 had at least 3 pain-related hospitalizations or emergency department visits within 12 months, and 570 had at least 3 months of coverage after the third episode.
Among those 570 patients, 86 (15%) were treated with HU within 3 months of their third encounter. The percentage of treated patients increased slightly to 18% at 6 months and to 23% at 12 months.
The researchers noted that there are several barriers to HU treatment, including fear of adverse events, lack of clinician training, and failure to engage in shared decision-making.
The team also pointed out that their data do not include the uninsured or publicly insured population, which may have more limited access to healthcare or awareness of treatment options than the patients studied. So these findings may not be representative of the entire US population with SCA and may be a conservative estimate of the HU treatment gap.
To address this gap, it may be necessary to enhance patient outreach and clinician training and develop healthcare quality measures aimed at increasing the use of HU for all patients who would benefit, the researchers said.
Photo by Zak Hubbard
Results of a retrospective study reinforce the idea that hydroxyurea (HU) is underused in US patients with sickle cell anemia (SCA).
Researchers analyzed data from an insurance claims database and identified 570 patients with probable SCA who were available for follow-up and likely would have benefitted from receiving HU.
Less than a quarter of those patients actually received the drug within a year of their third visit to a hospital seeking treatment for pain crises.
The researchers noted that these data may not be representative of the US population because the analysis does not include uninsured patients or publicly insured patients.
Nicolas Stettler, MD, of the Lewin Group in Falls Church, Virginia, and his colleagues conducted this research and reported the results in a letter to JAMA.
The researchers noted that the 2014 National Heart, Lung, and Blood Institute guidelines recommend using HU to treat all adults with SCA who experience 3 or more moderate-to-severe pain crises within a year. This is a “strong” recommendation based on high-quality evidence reviewed in 2008.
Despite this recommendation, it is thought that HU is underused, although the extent of its use has been unclear.
With that in mind, Dr Stettler and his colleagues examined the use of HU when indicated for SCA in the Optum Normative Health Informatics database. This database is a nationwide sample of commercial health and pharmacy claims from more than 36 million residents in all 50 states and Washington, DC.
The researchers identified adults ages 18 and older with 1 or more inpatient or outpatient claims for SCA between January 2009 and June 2013.
The team selected patients when they had 3 or more hospitalizations, emergency department visits, or both within 12 months that included 1 of the 5 most frequent diagnosis codes used for patients with SCA and pain crises.
Treatment was defined as filling 1 or more HU prescriptions during the 3, 6, or 12 months of continued enrollment following the third episode.
Of the enrolled population (n=26,631,901), the researchers identified 2086 adults with probable SCA. Of these patients, 677 had at least 3 pain-related hospitalizations or emergency department visits within 12 months, and 570 had at least 3 months of coverage after the third episode.
Among those 570 patients, 86 (15%) were treated with HU within 3 months of their third encounter. The percentage of treated patients increased slightly to 18% at 6 months and to 23% at 12 months.
The researchers noted that there are several barriers to HU treatment, including fear of adverse events, lack of clinician training, and failure to engage in shared decision-making.
The team also pointed out that their data do not include the uninsured or publicly insured population, which may have more limited access to healthcare or awareness of treatment options than the patients studied. So these findings may not be representative of the entire US population with SCA and may be a conservative estimate of the HU treatment gap.
To address this gap, it may be necessary to enhance patient outreach and clinician training and develop healthcare quality measures aimed at increasing the use of HU for all patients who would benefit, the researchers said.
Study sheds new light on decitabine
Image by Christoph Bock
A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a
patient’s cancer stage and response to treatment.
Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.
In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.
The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.
“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”
Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.
Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.
Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.
When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.
The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.
To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.
“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”
Image by Christoph Bock
A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a
patient’s cancer stage and response to treatment.
Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.
In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.
The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.
“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”
Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.
Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.
Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.
When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.
The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.
To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.
“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”
Image by Christoph Bock
A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a
patient’s cancer stage and response to treatment.
Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.
In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.
The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.
“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”
Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.
Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.
Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.
When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.
The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.
To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.
“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”
HL survivors have long-term risk of cardiovascular disease
Photo by Rhoda Baer
Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.
Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.
However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.
So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.
The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.
The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.
The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.
At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.
The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).
HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.
HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.
HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.
The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.
The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.
The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.
The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.
Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.
A commentary related to this research is available in JAMA Internal Medicine as well.
Photo by Rhoda Baer
Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.
Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.
However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.
So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.
The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.
The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.
The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.
At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.
The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).
HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.
HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.
HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.
The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.
The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.
The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.
The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.
Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.
A commentary related to this research is available in JAMA Internal Medicine as well.
Photo by Rhoda Baer
Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.
Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.
However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.
So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.
The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.
The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.
The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.
At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.
The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).
HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.
HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.
HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.
The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.
The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.
The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.
The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.
Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.
A commentary related to this research is available in JAMA Internal Medicine as well.
MM drug met accelerated approval requirements
Photo courtesy of the CDC
Celgene Corporation has fulfilled the requirements for accelerated approval of pomalidomide (Pomalyst) in the US, based on results from the phase 3 MM-003 trial.
The trial showed that pomalidomide in combination with dexamethasone can improve survival in patients with relapsed or refractory multiple
myeloma (MM).
A drug can be granted accelerated approval in the US based on a surrogate endpoint thought to predict clinical benefit.
To retain approval from the US Food and Drug Administration (FDA), the drug must demonstrate an actual clinical benefit.
In 2013, the FDA granted pomalidomide accelerated approval for use in combination with dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and have demonstrated disease progression on or within 60 days of completing their last therapy.
The FDA’s approval was based on results from a phase 2 trial known as MM-002. The trial showed that pomalidomide plus dexamethasone can improve the overall response rate in relapsed/refractory MM patients when compared to pomalidomide alone.
About 29% of patients in the pomalidomide-dexamethasone arm achieved a partial response or better, compared to about 7% of patients in the pomalidomide-alone arm.
Now, results of the MM-003 trial have shown that pomalidomide plus low-dose dexamethasone can improve progression-free survival and overall survival in relapsed/refractory MM patients, when compared to high-dose dexamethasone alone.
The median progression-free survival was 3.6 months in the pomalidomide-dexamethasone arm and 1.8 months in the dexamethasone arm (P<0.001). And the median overall survival was 12.4 months and 8 months, respectively (P=0.009).
These outcomes suggest pomalidomide, in combination with dexamethasone, provides a clinical benefit for previously treated MM patients, which fulfills the requirements for accelerated approval. So the drug’s label has been updated to reflect his change.
For more details on pomalidomide, see the full prescribing information.
Photo courtesy of the CDC
Celgene Corporation has fulfilled the requirements for accelerated approval of pomalidomide (Pomalyst) in the US, based on results from the phase 3 MM-003 trial.
The trial showed that pomalidomide in combination with dexamethasone can improve survival in patients with relapsed or refractory multiple
myeloma (MM).
A drug can be granted accelerated approval in the US based on a surrogate endpoint thought to predict clinical benefit.
To retain approval from the US Food and Drug Administration (FDA), the drug must demonstrate an actual clinical benefit.
In 2013, the FDA granted pomalidomide accelerated approval for use in combination with dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and have demonstrated disease progression on or within 60 days of completing their last therapy.
The FDA’s approval was based on results from a phase 2 trial known as MM-002. The trial showed that pomalidomide plus dexamethasone can improve the overall response rate in relapsed/refractory MM patients when compared to pomalidomide alone.
About 29% of patients in the pomalidomide-dexamethasone arm achieved a partial response or better, compared to about 7% of patients in the pomalidomide-alone arm.
Now, results of the MM-003 trial have shown that pomalidomide plus low-dose dexamethasone can improve progression-free survival and overall survival in relapsed/refractory MM patients, when compared to high-dose dexamethasone alone.
The median progression-free survival was 3.6 months in the pomalidomide-dexamethasone arm and 1.8 months in the dexamethasone arm (P<0.001). And the median overall survival was 12.4 months and 8 months, respectively (P=0.009).
These outcomes suggest pomalidomide, in combination with dexamethasone, provides a clinical benefit for previously treated MM patients, which fulfills the requirements for accelerated approval. So the drug’s label has been updated to reflect his change.
For more details on pomalidomide, see the full prescribing information.
Photo courtesy of the CDC
Celgene Corporation has fulfilled the requirements for accelerated approval of pomalidomide (Pomalyst) in the US, based on results from the phase 3 MM-003 trial.
The trial showed that pomalidomide in combination with dexamethasone can improve survival in patients with relapsed or refractory multiple
myeloma (MM).
A drug can be granted accelerated approval in the US based on a surrogate endpoint thought to predict clinical benefit.
To retain approval from the US Food and Drug Administration (FDA), the drug must demonstrate an actual clinical benefit.
In 2013, the FDA granted pomalidomide accelerated approval for use in combination with dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and have demonstrated disease progression on or within 60 days of completing their last therapy.
The FDA’s approval was based on results from a phase 2 trial known as MM-002. The trial showed that pomalidomide plus dexamethasone can improve the overall response rate in relapsed/refractory MM patients when compared to pomalidomide alone.
About 29% of patients in the pomalidomide-dexamethasone arm achieved a partial response or better, compared to about 7% of patients in the pomalidomide-alone arm.
Now, results of the MM-003 trial have shown that pomalidomide plus low-dose dexamethasone can improve progression-free survival and overall survival in relapsed/refractory MM patients, when compared to high-dose dexamethasone alone.
The median progression-free survival was 3.6 months in the pomalidomide-dexamethasone arm and 1.8 months in the dexamethasone arm (P<0.001). And the median overall survival was 12.4 months and 8 months, respectively (P=0.009).
These outcomes suggest pomalidomide, in combination with dexamethasone, provides a clinical benefit for previously treated MM patients, which fulfills the requirements for accelerated approval. So the drug’s label has been updated to reflect his change.
For more details on pomalidomide, see the full prescribing information.
Drug can prevent bleeding in kids with hemophilia A
A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.
Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.
None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.
The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.
The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.
The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.
The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.
About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.
Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.
About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.
Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.
A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.
Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.
None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.
The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.
The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.
The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.
The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.
About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.
Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.
About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.
Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.
A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.
Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.
None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.
The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.
The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.
The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.
The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.
About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.
Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.
About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.
Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.
Chemotherapy drugs recalled in US
Photo by Bill Branson
The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.
Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a
recall of these lots to the hospital/user level.
To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.
Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.
Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.
Recall details
The following drugs are included in this recall:
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
- Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
- Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273; Expiration date: 05/2016
- Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
- Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
- Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.
Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.
Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.
Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.
Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.
Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.
Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.
Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.
Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
Photo by Bill Branson
The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.
Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a
recall of these lots to the hospital/user level.
To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.
Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.
Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.
Recall details
The following drugs are included in this recall:
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
- Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
- Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273; Expiration date: 05/2016
- Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
- Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
- Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.
Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.
Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.
Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.
Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.
Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.
Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.
Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.
Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
Photo by Bill Branson
The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.
Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a
recall of these lots to the hospital/user level.
To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.
Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.
Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.
Recall details
The following drugs are included in this recall:
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
- Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
- Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
- Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273; Expiration date: 05/2016
- Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
- Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
- Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.
Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.
Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.
Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.
Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.
Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.
Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.
Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.
Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.
CDK inhibitor proves active against AML, ALL
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
Meeting plasma transfusion guideline is feasible
Photo by Cristina Granados
High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.
For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.
This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.
So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.
PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.
Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.
The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.
The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.
Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.
“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.
Photo by Cristina Granados
High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.
For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.
This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.
So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.
PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.
Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.
The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.
The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.
Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.
“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.
Photo by Cristina Granados
High-volume trauma centers can provide consistent, rapid delivery of universal-donor plasma to massively hemorrhaging patients without excessive wastage, results of the PROPPR trial suggest.
For this study, researchers assessed the feasibility of the 2013 guidelines issued by the American College of Surgeons, which recommend that universal-donor products be immediately available upon the arrival of severely injured patients.
This recommendation may be outside the capabilities of many facilities, but it is likely to become the expected standard in the near future, the researchers said.
So Deborah Novak, MD, of the University of Arizona in Tucson, and her colleagues tested the feasibility of following the guidelines and reported their findings in Transfusion.
PROPPR was a randomized trial in which the researchers compared survival after the transfusion of 2 different blood component ratios in patients with traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of a request.
Twelve Level 1 trauma centers were involved in the trial. Participants collected data on the blood components transfused and the amount of time it took to deliver those products, but they focused primarily on plasma.
The researchers evaluated the adequacy of site plans by comparing the blood availability times to study goals and the American College of Surgeons guidelines.
The 680 patients in this trial received about 4700 units of plasma. Eleven of the sites consistently delivered 6 units of thawed, universal-donor plasma to their trauma-receiving unit within the required 10 minutes. The sites were able to deliver 12 units of plasma within 20 minutes.
Three sites used blood group A plasma instead of AB for massive transfusion and did not see any complications. None of the sites experienced shortages of AB plasma that limited enrollment. Two of the sites reported wasting nearly 25% of the AB plasma prepared.
“We hope the descriptions of the various ways in which centers fulfilled the requirement of delivering blood components to the bedside within 10 minutes inspire other facilities to devise the most effective way for their own circumstances,” Dr Novak said.
miR expression may predict long-term prognosis in DLBCL
Photo courtesy of NIH
MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in
Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.
However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.
“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.
Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.
Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).
The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.
They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.
And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.
The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.
Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.
The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.
The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).
Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.
Photo courtesy of NIH
MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in
Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.
However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.
“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.
Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.
Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).
The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.
They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.
And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.
The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.
Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.
The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.
The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).
Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.
Photo courtesy of NIH
MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in
Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.
However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.
“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.
Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.
Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).
The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.
They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.
And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.
The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.
Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.
The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.
The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).
Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.
Malaria vaccine candidate proves somewhat effective
Photo by Caitlin Kleiboer
The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.
The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.
On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.
“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.
“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”
Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.
The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.
Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.
Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).
In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.
Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.
In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.
Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.
RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.
“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”
Photo by Caitlin Kleiboer
The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.
The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.
On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.
“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.
“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”
Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.
The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.
Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.
Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).
In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.
Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.
In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.
Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.
RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.
“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”
Photo by Caitlin Kleiboer
The malaria vaccine candidate RTS,S/AS01 is somewhat effective in young African children for up to 4 years after vaccination, according to final data from a phase 3 trial.
The vaccine proved more effective against clinical and severe malaria in children than in young infants, but efficacy waned over time in both age groups.
On the other hand, a booster dose of RTS,S/AS01 increased the average number of malaria cases prevented in children and infants.
“Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01,” said Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine in the UK.
“An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose.”
Dr Greenwood and his colleagues disclosed these data in The Lancet. The research was funded by GlaxoSmithKline Biologicals SA, the company developing RTS,S/AS01, and the PATH Malaria Vaccine Initiative.
The trial included 15,459 young infants (aged 6 weeks to 12 weeks at first vaccination) and children (5 months to 17 months at first vaccination) from 11 sites across 7 sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and United Republic of Tanzania) with varying levels of malaria transmission.
Earlier results from this trial, at 18 months of follow-up, showed efficacy of about 46% against clinical malaria in children and around 27% among young infants. Vaccine efficacy is defined as the reduction in the incidence of disease among participants who receive the vaccine compared to the incidence among participants who do not.
Dr Greenwood and his colleagues followed the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose.
Participants were each vaccinated 3 times with RTS,S/AS01, with or without a booster dose 18 months later, or given 4 doses of a comparator vaccine (control group).
In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.
Without a booster dose, the vaccine was not significantly effective against severe malaria in this age group. However, in children given a booster dose, the overall protective efficacy against severe malaria was 32% and 35% against malaria-associated hospitalizations.
In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years of follow-up. There was no significant protection against severe disease in infants.
Meningitis occurred more frequently in children given RTS,S/AS01 than in children given the control vaccine. There were 11 cases of meningitis among children who received a booster, 10 cases among children who did not receive a booster, and 1 case among children in the control group.
RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01. The incidence of other serious adverse events was similar in all the groups.
“The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data,” Dr Greenwood said. “If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease.”